Chemoattractant cytokines, Chemoattractant cytokines or chemokines are a family of proinflammatory mediators that are released by a wide variety of cells to promote recruitment and activation of cells such as T and B lymphocytes, eosinophils, basophils, and neutrophils (Luster et al. New Eng. J. Med, 1998, 338, 436). The chemokines are related in primary structure and contain four conserved cysteines, which form disulfide bonds. The chemokine family includes the C-X-C chemokines (α-chemokines), and the C-C chemokines (β-chemokines), in which the first two conserved cysteines are separated by an intervening residue, or are adjacent, respectively (Baggiolini, M. and Dahinden, C. A., Immunology Today, 1994, 15, 127).
Chemokines exert their biological activity by binding to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (Horuk, Trends Pharm. Sci. 1994, 15, 159) which are termed “chemokine receptors”. On binding their cognate ligands, chemokine receptors then transduce signals important for the development and trafficking of specific leukocyte subsets (Baggiolini, et. al., Nature 1994, 15, 365). The chemokines and their cognate receptors have been implicated as being important mediators of inflammatory, and allergic diseases, disorders, and conditions, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis (see, Carter, Current Opinion in Chemical Biology 2002, 6, 510; Trivedi et al., Ann. Reports Med. Chem. 2000, 35, 191; Saunders et al., Drug Disc. Today 1999, 4, 80; and Premack et al., Nature Medicine, 1996, 2, 1174). Chemokines and their cognate receptors have also been implicated in the development of cancer and osteolytic bone disorders (see, Leukemia 2003, 17, 203; J. Bone Miner. Res. 2002, 19, 2065; J. Cell. Biochem. 2002, 87, 386; J. Cell. Physiol. 2000, 183, 196; Exp. Hematol. 2005, 33, 272; J. Clin. Invest. 2001, 108, 1833; Cancer 2003, 97, 813; Blood 2003, 102, 311).
Accordingly, agents that block the interaction of chemokines with their cognate receptors are useful in treating inflammatory, allergic, and autoimmune diseases, disorders, or conditions, and are also useful in the treatment of cancer and osteolytic bone disorders caused by aberrant activation of leukocytes or lymphocytes.
U.S. patent application No. US2002/0169155 and International Publication Number WO 03/045942, both entitled “Chemokine Receptor Antagonists and Methods of Use Thereof”, disclose compounds that exhibit an inhibitory effect on the chemokine receptor CCR1. These applications additionally disclose methods for the preparation of these compounds, pharmaceutical compositions containing these compounds, and methods for the prophylaxis and therapy of diseases, disorders, or conditions associated with aberrant leukocyte recruitment and/or activation, including but not limited to rheumatoid arthritis and multiple sclerosis.
(S)-4-(4-Chloro-phenyl)-1-{3-[7-(1-hydroxy-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-3,3-dimethyl-piperidin-4-ol (II) is also specifically disclosed:

The structure and synthesis of the free-base amorphous form of this compound is provided in the working examples in US2002/0169155 and WO 03/045942, and only a general discussion of a wide variety of salts is disclosed. These applications do not disclose specific salts or crystalline forms of (S)-4-(4-Chloro-phenyl)-1-{3-[7-(1-hydroxy-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-3,3-dimethyl-piperidin-4-ol (II).
When a compound crystallizes from a solution or slurry, it may crystallize with different spatial lattice arrangements, a property referred to as “polymorphism.” Each of the crystal forms is a “polymorph.” While polymorphs of a given substance have the same chemical composition, they may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, melting point, crystal shape, compaction behavior, flow properties, and/or solid state stability.
As described generally above, the polymorphic behavior of drugs can be of crucial importance in pharmacy and pharmacology. The differences in physical properties exhibited by polymorphs affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when it is one polymorph than when it is another polymorph) or mechanical changes (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). In addition, the physical properties of the crystal may be important in processing: for example, one polymorph might be more likely to form solvates that cause the solid form to aggregate and increase the difficulty of solid handling, or might be difficult to filter and wash free of impurities (i.e., particle shape and size distribution might be different between one polymorph relative to other).
While drug formulations having improved chemical and physical properties are desired, there is no predictable means for preparing new drug forms (e.g., polymorphs) of existing molecules for such formulations. These new forms would provide consistency in physical properties over a range of environments common to manufacturing and composition usage. In the instant case, no art describes a citrate salt of (S)-4-(4-Chloro-phenyl)-1-{3-[7-(1-hydroxy-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-3,3-dimethyl-piperidin-4-ol, and crystalline forms thereof. More particularly, no art describes a citrate salt of (S)-4-(4-Chloro-phenyl)-1-{3-[7-(1-hydroxy-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-3,3-dimethyl-piperidin-4-ol, and crystalline forms thereof, that have unexpected properties that are useful for large-scale manufacturing, pharmaceutical formulation, and storage.